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Peer-reviewedCC BY 4.0Chemistry (Weinheim an Der Bergstrasse, Germany)

4′‐ThioRNA Substitution and Sense‐Strand Segmentation for the Design of Functional Fully Modified siRNAs Targeting SARS‐CoV‐2

  • Yuhei Nogi1
  • Jun Tsukimoto1
  • Noriko Saito‐Tarashima1
  • Takaaki Koma2,3
  • Masako Nomaguchi2,3
  • Noriaki Minakawa1
  1. 1Graduate School of Pharmaceutical Science Tokushima University Tokushima Tokushima Japan
  2. 2Department of Microbiology, Graduate School of Medicine Tokushima University Tokushima Tokushima Japan
  3. 3Division of Interdisciplinary Research for Medicine and Photonics, Institute of Post‐LED Photonics Tokushima University Tokushima Tokushima Japan
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Abstract

Chemically modified small interfering RNAs (siRNAs) are proving to be highly effective as therapeutic agents, but the extent and positioning of chemical modifications must be carefully tuned because the RNA interference (RNAi) machinery imposes intrinsic constraints on siRNA architecture. Here, using a SARS‐CoV‐2‐targeting siRNA as a model, we have systematically investigated the positional and extent‐dependent tolerance of 4′‐thioRNA substitution within functional siRNAs. Single 4′‐thioRNA substitution was broadly tolerated across multiple positions, and complete substitution of either the sense or antisense strand preserved robust RNAi activity. In contrast, full substitution of both strands resulted in a pronounced loss of activity. Physicochemical analysis suggested that this loss arises from interference with cleavage and removal of the sense strand during loading of the RNA‐induced silencing complex (RISC). Sense‐strand segmentation was therefore applied to fully 4′‐thio‐modified siRNA to mimic the post‐cleavage state during RISC loading. This design partially restored RNAi activity, facilitating the development of fully 4'‐thio‐modified siRNAs with antiviral activity against SARS‐CoV‐2. Collectively, these findings expand the chemical space available for functional siRNA design.

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Cite

BibTeXRIS
BibTeX
@article{nogi20264thiorna,
  title = {{4′‐ThioRNA Substitution and Sense‐Strand Segmentation for the Design of Functional Fully Modified siRNAs Targeting SARS‐CoV‐2}},
  author = {Yuhei Nogi and Jun Tsukimoto and Noriko Saito‐Tarashima and Takaaki Koma and Masako Nomaguchi and Noriaki Minakawa},
  journal = {Chemistry (Weinheim an Der Bergstrasse, Germany)},
  year = {2026},
  month = aug,
  doi = {10.1002/chem.71507},
  url = {https://doi.org/10.1002/chem.71507},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - 4′‐ThioRNA Substitution and Sense‐Strand Segmentation for the Design of Functional Fully Modified siRNAs Targeting SARS‐CoV‐2
AU  - Yuhei Nogi
AU  - Jun Tsukimoto
AU  - Noriko Saito‐Tarashima
AU  - Takaaki Koma
AU  - Masako Nomaguchi
AU  - Noriaki Minakawa
PY  - 2026
DA  - 2026/08/03
JO  - Chemistry (Weinheim an Der Bergstrasse, Germany)
DO  - 10.1002/chem.71507
UR  - https://doi.org/10.1002/chem.71507
AB  - Chemically modified small interfering RNAs (siRNAs) are proving to be highly effective as therapeutic agents, but the extent and positioning of chemical modifications must be carefully tuned because the RNA interference (RNAi) machinery imposes intrinsic constraints on siRNA architecture. Here, using a SARS‐CoV‐2‐targeting siRNA as a model, we have systematically investigated the positional and extent‐dependent tolerance of 4′‐thioRNA substitution within functional siRNAs. Single 4′‐thioRNA substitution was broadly tolerated across multiple positions, and complete substitution of either the sense or antisense strand preserved robust RNAi activity. In contrast, full substitution of both strands resulted in a pronounced loss of activity. Physicochemical analysis suggested that this loss arises from interference with cleavage and removal of the sense strand during loading of the RNA‐induced silencing complex (RISC). Sense‐strand segmentation was therefore applied to fully 4′‐thio‐modified siRNA to mimic the post‐cleavage state during RISC loading. This design partially restored RNAi activity, facilitating the development of fully 4'‐thio‐modified siRNAs with antiviral activity against SARS‐CoV‐2. Collectively, these findings expand the chemical space available for functional siRNA design.
SN  - 0947-6539
SN  - 1521-3765
ER  -